Spiroannulated nucleosides and process for the preparation thereof

ABSTRACT

We claim a simple strategy for the synthesis of a collection of C(3′)-spirodihydroisobenzo-furannulated and C(3′)-spirodihydroisobenzo-furannulated nucleosides featuring a [2+2+2]-cyclotrimerization as the key reaction. The cyclotrimerization reactions are facile with the unprotected nucleosides having a diyne unit. When both alkynes of the diyne are terminal, the regioselectivity is poor. However, when one of the terminal alkynes is additionally substituted, the cyclotrimerizations are highly diastereoselective. Since the key bicycloannulation is the final step, this strategy provides flexibility in terms of the alkynes and is thus amenable for the synthesis of a focussed small molecule library.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a divisional of U.S. patent application Ser. No.13/976,872, filed Jun. 27, 2013, which is a Section 371 National StageApplication of International Application No. PCT/IB2011/055968, filedDec. 27, 2011 and published as WO/2012/090155 A1 on Jul. 5, 2012, inEnglish, which claims priority of Indian Application No. 3103/DEL/2010,filed Dec. 27, 2010, the contents of which are hereby incorporated byreference in their entirety.

FIELD OF INVENTION

The present invention relates to Spiroannulated Nucleosides and processfor the preparation thereof. More particularly, the present inventionprovides a library of synthetically prepared spiroannulated nucleosidesas potential anti-cancer and anti-viral candidates.

BACKGROUND AND PRIOR ART

Nucleosides are glycosylamines consisting of a nucleobase (oftenreferred to as simply base) bound to a ribose or deoxyribose sugar via abeta-glycosidic linkage. In medicine several nucleoside analogues areused as antiviral or as anticancer agents. Number of nuclearmodifications has been reported in the literature in which the sugarmoiety is locked in a certain conformation. However, access tocollections of the distinctive small molecules by modification of thesugar moiety in a nucleoside is an important feature in the realm ofchemical genetics and for identifying new therapeutic candidates.

Diversity oriented synthesis (DOS) conceptualized by Schreiber hascertainly provided an impetus to rapidly accessing the complexsmall-molecule libraries. However, flexibility in modulating thestructural characteristics remains the cornerstone of a successful hitto lead exploration. A strategy that integrates the conceptualadvantages of DOS and the manipulation of chemical functionality in atarget oriented synthesis could be a valuable tool in new drug discoveryprograms.

Designing a new class of conformationally restricted nucleosides basedon modification of the glycosyl moiety by spirocyclicannulation has nowbeen recognized as an attractive strategy for delivering moleculardiversity.

In this respect, cycloaddition reactions particularly [2+2+2]alkynecyclotrimerization reaction in presence of a transition metalcatalyst on sugar templates have been studied and considered to bestrategically useful for synthesizing library of small molecules. Theunique characteristic property of [2+2+2]-alkynecyclotrimerization isits high synthetic efficiency (with the formation of several C—C and/orC-heteroatom bonds in a single step), complete atom-economy, and theavailability of a wide range of catalysts that can tolerate a myriad ofprotecting/functional groups.

Utilizing [2+2+2]-alkyne cyclotrimerization for building modified sugar(spiro)-annulated tricyclic homochiral scaffold and further utilizationof these scaffolds for the synthesis of tricyclic nucleosides remains animportant therapeutic approach for developing small molecules thatcontrol genetic disorders or infections.

Cyclotrimerization reaction on sugar templates has been less exploredand limited mainly to the synthesis of C-aryl glycosides. [McDonald, F.E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc. 1995, 117,6605-6606; Yamamoto, Y.; Saigoku, T.; Ohgai, T.; Nishiyamaa, H.; Itohb,K. Chem. Commun. 2004, 2702-2703; Yamamoto, Y.; Hashimoto, T.; Hattori,K.; Kikuchi, M.; Nishiyama, H. Org. Lett. 2006, 8, 3565-3568; Novak, P.;Pohl, R.; Kotora, M.; Hocek, M. Org. Lett. 2006, 8, 2051-2054]. An earlyexample in this context is an expedient synthesis of spirocyclicC-arylglycoside whose frame work is closely related to that ofpapulacandins by McDonald and co-workers [McDonald, F. E.; Zhu, H. Y.H.; Holmquist, C. R. J. Am. Chem. Soc. 1995, 117, 6605-6606]. Yamamotoand co-workers [Yamamoto, Y.; Saigoku, T.; Ohgai, T.; Nishiyamaa, H.;Itohb, K. Chem. Commun. 2004, 2702-2703; Yamamoto, Y.; Hashimoto, T.;Hattori, K.; Kikuchi, M.; Nishiyama, H. Org. Lett. 2006, 8, 3565-3568]and Kotora and co-workers [Kotora, M.; Hocek, M. Org. Lett. 2006, 8,2051-2054] have independently reported a[2+2+2]-alkynecyclotrimerization approach for the synthesis of C-arylribosides and C-aryldeoxyribosides, respectively. A[2+2+2]-alkynecyclotrimerization on a sugar derived building block forconstructing enantiomeric tricyclicmolecular skeletons consisting ofisochroman units is disclosed by Ramana, C. V.; Suryawanshi, S. B.Tetrahedron Lett. 2008, 49, pg 445448.

Article titled “Carbohydrate-Based Molecular Scaffolding” by IngridVelter et. al in Journal of Carbohydrate Chemistry, 25:97-138, 2006having DOI: 10.1080/07328300600733020 discloses the use of modifiedcarbohydrates, such as sugar amino acids (SAA), iminosugars andpolycyclic derivatives, as scaffolds for the generation of bioactivecompounds, and the use of carbohydrates as building blocks or ligandsfor the production of polymers for biomedical applications.

Article titled “A simple cobalt catalyst system for the efficient andregioselective cyclotrimerisation of alkynes” by Gerhard Hilt et. al inChem. Commun., 2005, 1474-1475 having DOI: 10.1039/b417832g describesthe intermolecular cyclotrimerisation of terminal and internal alkynescatalysed by simple cobalt complexes such as a CoBr2 (diimine) undermild reaction conditions when treated with zinc and zinc iodide withhigh regioselectivity in excellent yields.

Article titled “Selective synthesis of C-arylglycosides viaCpRuCl-catalyzed partially intramolecular cyclotrimerizations ofC-alkynylglycosides” by Y. Yamamoto, T. Saigoku, in Org. Biomol. Chem,2005, 3, 1768-1775 having DOI:10.1039/b503258j describes synthesis ofC-arylglycosides by means of the CpRuCl-catalyzed [2+2+2]-cycloadditionof α,ω-diynes with C-alkynylglycosides under mild reaction conditions.The functional group compatibility of the ruthenium catalysis towards awide variety of functional groups allows synthesis of interestingC-arylglycosides including anthraquinone C-glycosides, bis(C-glycosyl)benzenes as well as C-arylglycoside amino acids.

Article titled “Chemo- and regioselective crossed alkynecyclotrimerisation of 1,6-diynes with terminal monoalkynes mediated byGrubbs' catalyst or Wilkinson's catalyst” by Bernhard Witulski et. al inChem. Commun., 2000, 1965-1966 having DOI: 10.1039/b005636g; disclosescrossed alkyne cyclotrimerisations mediated by Grubbs' catalyst[RuCl₂(NCHPh)(PCy₃)₂] which allows the efficient synthesis of4,6-substituted indolines with high regioselectivity, and iscomplementary to alkyne cyclotrimerisations mediated by Wilkinson'scatalyst [RhCl(PPh₃)₃] allowing the regioselective synthesis of thecorresponding 4,5-substituted isomers.

Several approaches are documented for the modification of nucleosides.

Article titled “Preparation of Highly Substituted 6-ArylpurineRibonucleosides by Ni-Catalyzed Cyclotrimerization. Scope of theReaction” by Pavel Turek et. al in J. Org. Chem., 2006, 71, 8978-8981having DOI: 10.1021/jo061485y describes transition metal complexcatalyzed cocyclotrimerization of protected alkynyl purineribonucleosides with various diynes to give series of 6-arylpurinenucleosides that were further deprotected to free nucleosides.Cyclotrimerizations were obtained with a catalytic systemNi(cod)2/2PPh3. CoBr(PPh3)3 is employed as a catalyst forcyclotrimerization of with dipropargyl ether. In addition, Ni catalysisis used for direct cyclotrimerization of unprotectedalkynylpurineribonucleosides to the corresponding6-arylpurinylribosides.

Article titled “Synthesis of C-Aryldeoxyribosides by[2+2+2]-Cyclotrimerization Catalyzed by Rh, Ni, Co, and Ru Complexes” byPetrNovák, et. al in Org. Lett., 2006, 8, 2051-2054 havingDOI:10.1021/o1060454m describes a novel approach to the synthesis offunctionalized C-nucleosides wherein cyclotrimerization ofC-alkynyldeoxyriboside with a variety of substituted 1,6-heptadiynes iscarried out to obtain the corresponding C-aryldeoxyribosides in presenceof catalysts selected from various transition metal complexes (Rh, Ir,Co, Ru, and Ni) preferably, RhCl(PPh₃)₃.

Article titled “The isochroman- and 1,3-dihydroisobenzofuran-annulationon carbohydrate templates via [2+2+2]-cyclotrimerization and synthesisof some tricyclic nucleosides” Tetrahedron, 2010, 66, pg 6085. disclosesthe feasibility of cyclotrimerization of sugar derived diynes and shownthat the resultant products can be transformed to the tricyclic andC(3′)-spirobenzoisofuran-annulated nucleosides following a sequence ofchemical transformations. However, the spiro-annulated nucleosidesreported contains a pentopyranose unit (6-membered sugar unit). Also,this strategy is not sufficiently effective as the number of compoundsto be accessed is restricted by the limited number of nucleobasesavailable which are introduced at the penultimate step of the synthesis.In addition, it may require additional steps if one intends to placesensitive functional groups on the isobenzofuran ring. This has promptedus to look for an alternative approach which can effectively address thelibrary size and the ease of alteration of the functional groups on theisobenzofuran ring. This has led us into the exploration of the keyC(3′)-spiroannulation as the final step by means of[2+2+2]-cyclotrimerization of completely free nucleoside-diynes withalkynes which is the main theme of the current patent application andalso we address the selective synthesis of spiroannulated nucleosideshaving the furanoside ring also.

The prior art approaches, however, have in general been executed in atarget oriented way (one scheme one nucleoside). This causes a seriouslimitation in the collection of spironucleosides as each modificationneeds to be attended separately from the beginning of the synthesis.

OBJECTIVE OF THE PRESENT INVENTION

The main objective of the present invention relates to SpiroannulatedNucleosides and process for the preparation thereof.

Another object of the present invention is to develop a strategy thatamply provides the spiro-annulation on sugar unit of nucleosides withenormous flexibility to modulate the substituents and properties of thenewly annulated bicyclic ring systems.

Another object of the present invention is to provide spiroannulation onthe sugar unit of nucleoside template involving intermolecular [2+2+2]cyclotrimerisation of the penultimate nucleoside diyne with easilyaccessible alkynes.

Another object of the present invention is to provide a process for thepreparation of Spiroannulated Nucleosides.

Yet another object of the present invention is to obtain a library ofsynthetically prepared spiroannulated nucleosides.

Another object of the invention is to append the isochroman ordihydroisobenzofuran structural unit on the sugar template of thenucleoside by spiroannulation.

Another object of the current invention is to apply a structurallysimplifying transform(s) at the beginning of the retrosynthetic schemewhich comprises multiple bond disconnections resulting in a couple ofretrons.

SUMMARY OF INVENTION

Accordingly, the present invention provides library of spiroannulatedNucleosides and process for the preparation thereof. The presentinvention relates to intermolecular [2+2+2] cyclotrimerization reactionof the penultimate nucleoside diynes with symmetrical or unsymmetricalalkynes to obtain enantiopure tricyclic systems of the general FormulaI;

where, R (in the base) is selected from H, C₁-C₄ alkyl, halogen, OR NHR′(R′=H, COCH₃, CO₂ ^(t)Bu); Q=H with the proviso that C—N double bond isabsent, C—Z double bond is present and Z is O; Z is NH₂ with the provisothat C—Z double bond is absent, Q≠H; Z is O with the proviso that C—Ndouble bond is absent;

A and A′ are selected from H, lower alkyl, —OH, —OAc CH₂OH, —CH₂OAc,—CH₂OPiv, —CH₂OTBS; m and n are integers 0,1

A″ and A′″ are selected from 1,3-dihydroisobenzofuran (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b),

where R, R′, R″ are selected from H, —OH, halo group, —CH₂OH, —CH₂OAc,—COOH, —COOMe, C1-C30 straight or branched alkyl group, optionallysubstituted with halogen or —OH or —NH₂ or —NPhth; phenyl groupoptionally substituted with halogen, amino, nitro, C1-C6 alkyl;

with the proviso that when n=1[i.e(CH₂)n=1] and where m=0[i.e(CH₂)m=0],A′″ is absent and A″ is 1,3-dihydro isobenzofuran (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), directlyannulated at C-3, A and A′ are selected from H, lower alkyl, —OH, —OAc,—CH2OH—CH₂OAc, —CH₂OPiv, —CH₂OTBS,; and R, R′ and R″ in 1,3-dihydroisobenzofuran (1a) or isochroman [3,4-dihydro-1H-benzo[c]pyran]represented by the formula (1b) are selected from H, —OH, halo group,—CH₂OH, —CH₂OAc, —COOH, —COOMe, C1-C30 straight or branched alkyl group,optionally substituted with halogen or —OH or —NH2 or —NPhth; phenylgroup optionally substituted with halogen, amino, nitro, C 1-C6 alkyl; R(in the base) is selected from H, C1-C4 alkyl, halogen; Q=H with theproviso that C—N double bond is absent, C—Z double bond is present and Zis O; Z is NH₂ with the proviso that C—Z double bond is absent, Q≠H; Zis O with the proviso that C—N double bond is absent;

with the proviso that when both n=1 and m=1, A″ is absent and A″′ isselected from 1,3-dihydroisobenzofuran of formula (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), A and A′are selected from H, lower alkyl, —OH, —OAc, —CH₂OH, —CH₂OAc; R, R′ andR″ in 1,3-dihydroisobenzofuran of formula (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b) areselected from H, —OH, —OAc, halo group, —CH2OH, —CH2OAc, —COOH, —COOMe,C1-C30 straight or branched alkyl group, optionally substituted withhalogen or —OH or —NH2 or —NPhth; phenyl group optionally substitutedwith halogen, amino, nitro, C1-C6 alkyl; R (in the base) is selectedfrom H, C1-C4 alkyl, halogen; Q=H with the proviso that C—N double bondis absent, C—Z double bond is present and Z is O; Z is NH₂ with theproviso that C—Z double bond is absent, Q≠H; Z is O with the provisothat C—N double bond is absent;

with the proviso that both A and A″ can form together1,3-dihydroisobenzofuran (1a) where R, R′ and R″, are selected from H,—OH, halo group, —CH₂OH, —CH₂OAc, —COOH, —COOMe, C1-C30 straight orbranched alkyl group, optionally substituted with halogen or —OH or —NH₂or —NPhth; phenyl group optionally substituted with halogen, amino,nitro, C1-C6 alkyl when m=0[i.e(CH2)m=0], A″′ is absent and A′ isselected from H, lower alkyl, —OH, —OAc, —CH₂OH, —CH₂OAc, —CH₂OMe,—CH₂OEt, phenyl optionally substituted with halogen, amino, nitro, C1-C6alkyl.

In an aspect, a library of spiro annulated nucleosides is obtained bymodification on the sugar moiety of the nucleoside by[2+2+2]-cyclotrimerization of the penultimate nucleoside diyne withsymmetrical and unsymmetrical alkyne in presence of Rh or Ru complexcatalyst in good yield.

In an embodiment of the present invention the Spiro annulated nucleosideof general formula I, wherein the structural formulae of therepresentative compounds are

18 R = R′ = H 19 R = R′ = H 20 R = R′ = H 24 R = R′ = CH₂OAc 25 R = R′ =CH₂OAc 26 R = R′ = CH₂OAc 30 R or R′ = C₅H₁₁ 31 R or R′ = C₅H₁₁ 32 R orR′ = C₅H₁₁

21 R = R′ = H 22 R = R′ = H 23 R = R′ = H 27 R = R′ = CH₂OAc 28 R = R ′=CH₂OAc 29 R = R′ = CH₂OAc 33 R or R′ = C₅H₁₁ 34 R or R′ = C₅H₁₁ 35 R orR′ = C₅H₁₁

54 R′ = —Ph 60 R′ = —Ph 64 R′ = —Ph (dr = 7:1) 55 R′ = —^(n)C₆H₁₃ 61 R′= —^(n)C₆H₁₃ 65 R′ = —^(n)C₆H₁₃ 56 R′ = —^(n)C₂₁H₄₃ 62 R′ = —^(n)C₂₁H₄₃66 R′ = —^(n)C₂₁H₄₃ 57 R′ = —(CH₂)₃Cl 63 R′ = —(CH₂)₃Cl 67 R′ =—(CH₂)₃Cl 58 R′ = —CH₂NPht 59 R′ = m-(Ar—NH₂)

78 R′ = H 85 R′ = H 92 R′ = H 79 R′ = —Ph 86 R′ = —Ph 93 R′ = —Ph 80 R′= —^(n)C₆H₁₃ 87 R′ = —^(n)C₆H₁₃ 94 R′ = —^(n)C₆H₁₃ 81 R′ = —^(n)C₂₁H₄₃88 R′ = —^(n)C₂₁H₄₃ 95 R′ = —^(n)C₂₁H₄₃ 82 R′ = —(CH₂)₃Cl 89 R′ =—(CH₂)₃Cl 96 R′ = —(CH₂)₃Cl 83 R′ = —CH₂NPht 90 R′ = —CH₂NPht 97 R′ =—CH₂NPht 84 R′ = m-(Ar—NH₂) 91 R′ = m-(Ar—NH₂) 98 R′ = m-(Ar—NH₂)

99 R′ = H 106 R′ = H 113 R′ = H 100 R′ = —Ph 107 R′ = —Ph 114 R′ = —Ph101 R′ = —^(n)C₆H₁₃ 108 R′ = —^(n)C₆H₁₃ 115 R′ = —^(n)C₆H₁₃ 102 R′ =—^(n)C₂₁H₄₃ 109 R′ = —^(n)C₂₁H₄₃ 116 R′ = —^(n)C₂₁H₄₃ 103 R′ = —(CH₂)₃Cl110 R′ = —(CH₂)₃Cl 117 R′ = —(CH₂)₃Cl 104 R′ = —CH₂NPht 111 R′ =—CH₂NPht 118 R′ = —CH₂NPht 105 R′ = m-(Ar—NH₂) 112 R′ = m-(Ar—NH₂) 119R′ = m-(Ar—NH₂)

In another embodiment of the present invention the Spiro annulatednucleoside of general formula I is represented by the group of thefollowing compounds

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil (01):

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]thymine (02):

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]5-flurouracil(03):

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil (04):

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]thymine (05):

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]5-flurouracil (06):

1-[3-C-Phenylethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil(36):

1-[3-C-(1-Octynyl)-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil (37):

1-[3-C-Phenylethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil (38):

1-[3-C-Propynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil (74a):

1-[3-C-Phenylpropynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]thymine(74b):

1-[3-C-^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]5-flurouracil (74c):

1-[3-C-Propynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil (77a):

1-[3-C-Phenylpropynyl-3-O-(2-propynyl-β-D-ribopyranosyl]thymine (77b):

1-[3-C-^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]5-flurouracil(77c):

1-[3-C,3-O-(o-Phenylenemethylene)-β-D-ribofuranosyl]uracil (18):

1-[3-C,3-O-(o-Phenylenemethylene)-β-D-ribofuranosyl]thymine (19):

1-[3-C,3-O-(o-Phenylenemethylene)-β-D-ribofuranosyl]5-flurouracil (20):

1-[3-C,3-O-(o-Phenylenemethylene)-β-D-ribopyranosyl]uracil (21):

1-[3-C,3-O-(o-Phenylenemethylene)-β-D-ribopyranosyl]thymine (22):

1-[3-C,3-O-(o-Phenylenemethylene)-β-D-ribopyranosyl]5-flurouracil (23):

1-[3-C,3-O-{o-(3,4-Di-acetyloxymethyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(24):

1-[3-C,3-O-{o-(3,4-Di-acetyloxymethyl-phenylenemethylene}-β-n-ribofuranosyl]thymine(25):

1-[3-C,3-O-{o-(3,4-Di-acetyloxymethyl)-phenylenemethylene}-β-D-ribofuranosyl]5-flurouracil(26):

1-[3-C,3-O-{o-(3,4-Di-acetyloxymethyl)-phenylenemethylene}-β-D-ribopyranosyl]uracil(27):

1-[3-C,3-O-{o-(3,4-Di-acetyloxymethyl)-phenylenemethylene}-β-D-ribopyranosyl]thymine(28):

1-[3-C,3-O-{o-(3,4-Di-acetyloxymethyl)-phenylenemethylene}-β-D-ribopyranosyl]5-flurouracil(29):

1-[3-C,3-O-{o-(3/4-^(n)Pentyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(30):

1-[3-C,3-O-{o-(3/4-^(n)Pentyl)-phenylenemethylene}-β-D-ribofuranosyl]thymine(31):

1-[3-C,3-O-{o-(3/4-^(n)Pentyl)-phenylenemethylene}-β-D-ribofuranosyl]5-flurouracil(32):

1-[3-C,3-O-{o-(3/4-^(n)Pentyl)-phenylenemethylene}-β-D-ribopyranosyl]uracil(33):

1-[3-C,3-O-{o-(3/4-^(n)Pentyl)-phenylenemethylene}-β-D-ribopyranosyl]thymine(34):

1-[3-C,3-O-{o-(3/4-^(n)Pentyl)-phenylenemethylene}-β-D-ribopyranosyl]5-flurouracil(35):

1-[3-C,3-O-{o-(2,4-Diphenyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(54):

1-[3-C,3-O-{o-(2-Phenyl-4-^(n)hexyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(55):

1-[3-C,3-O-{o-(2-Phenyl-4-^(n)henicosyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(56):

1-[3-C,3-O-{o-(2-Phenyl-4-chloropropyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(57):

1-[3-C,3-O-{o-(2-Phenyl-4-phthalimidomethyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(58):

1-[3-C,3-O-{o-(2-Phenyl-4-(3-aminophenyl))-phenylenemethylene}-β-D-ribofuranosyl]uracil(59):

1-[3-C,3-O-{o-(2-^(n)Hexyl-4-phenyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(60):

1-[3-C,3-O-{o-(2-^(n)Hexyl-4-^(n)hexyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(61):

1-[3-C,3-O-{o-(2-^(n)Hexyl-4-^(n)henicosyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(62):

1-[3-C,3-O-{o-(2-^(n)Hexyl-4-chloropropyl)-phenylenemethylene}-β-D-ribofuranosyl]uracil(63):

1-[3-C,3-O-{o-(2,4-Diphenyl)-phenylenemethylene}-β-D-ribopyranosyl]uracil(64)

1-[3-C,3-O-{o-(2-phenyl-4-^(n)hexyl)-phenylenemethylene}-β-D-ribopyranosyl]uracil(65):

1-[3-C,3-O-{o-(2-phenyl-4-^(n)henicosyl)-phenylenemethylene}-β-D-ribopyranosyl]uracil(66):

1-[3-C,3-O-{o-(2-phenyl-4-chloropropyl)-phenylenemethylene}-β-D-ribopyranosyl]uracil(67):

1-[3-C,3-O-{o-Benzylmethylene}-β-D-ribofuranosyl]uracil (78)

1-[3-C,3-O-{o-(5-Phenyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil (79)

1-[3-C,3-O-{o-(5-^(n)Hexyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(80)

1-[3-C,3-O-{o-(5-^(n)henicosyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(81)

1-[3-C,3-O-{o-(5-chloropropyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(82)

1-[3-C,3-O-{o-(5-phthalimidomethyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(83)

1-[3-C,3-O-{o-[5-(3-aminophenyl)]-Benzylmethylene}-β-D-ribofuranosyl]uracil(84)

1-[3-C,3-O-{o-(3-Phenyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil (85)

1-[3-C,3-O-{o-(3-Phenyl-5-Phenyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(86)

1-[3-C,3-O-{o-(3-Phenyl-5-^(n)Hexyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(87)

1-[3-C,3-O-{o-(3-Phenyl-5-^(n)henicosyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(88)

1-[3-C,3-O-{o-(3-Phenyl-5-chloropropyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(89)

1-[3-C,3-O-{o-(3-Phenyl-5-phthalimidomethyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(90)

1-[3-C,3-O-{o-[3-Phenyl-5-(3-aminophenyl)]-Benzylmethylene}-β-D-ribofuranosyl]uracil(91)

1-[3-C,3-O-{o-(3-^(n)Hexyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(92)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-Phenyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(93)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-^(n)Hexyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(94)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-^(n)henicosyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(95)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-chloropropyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(96)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-phthalimidomethyl)-Benzylmethylene}-β-D-ribofuranosyl]uracil(97)

1-[3-C,3-O-{o-[3-^(n)Hexyl-5-(3-aminophenyl)]-Benzylmethylene}-β-D-ribofuranosyl]uracil(98)

1-[3-C,3-O-{o-Benzylmethylene}-β-D-ribopyranosyl]uracil (99)

1-[3-C,3-O-{o-(5-Phenyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil (100)

1-[3-C,3-O-{o-(5-^(n)Hexyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(101)

1-[3-C,3-O-{o-(5-^(n)henicosyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(102)

1-[3-C,3-O-{o-(5-chloropropyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(103)

1-[3-C,3-O-{o-(5-phthalimidomethyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(104)

1-[3-C,3-O-{o-[5-(3-aminophenyl)]-Benzylmethylene}-β-D-ribopyranosyl]uracil(105)

1-[3-C,3-O-{o-(3-Phenyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil (106)

1-[3-C,3-O-{o-(3-Phenyl-5-Phenyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(107)

1-[3-C,3-O-{o-(3-Phenyl-5-^(n)Hexyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(108)

1-[3-C,3-O-{o-(3-Phenyl-5-^(n)henicosyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(109)

1-[3-C,3-O-{o-(3-Phenyl-5-chloropropyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(110)

1-[3-C,3-O-{o-(3-Phenyl-5-phthalimidomethyl)-Benzylmethylene}-β-ribopyranosyl]uracil(111)

1-[3-C,3-O-{o-[3-Phenyl-5-(3-aminophenyl)]-Benzylmethylene}-β-D-ribopyranosyl]uracil(112)

1-[3-C,3-O-{o-(3-^(n)Hexyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(113)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-Phenyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(114)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-^(n)Hexyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(115)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-^(n)henicosyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(116)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-chloropropyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil (117)

1-[3-C,3-O-{o-(3-^(n)Hexyl-5-phthalimidomethyl)-Benzylmethylene}-β-D-ribopyranosyl]uracil(118)

1-[3-C,3-O-{o-[3-^(n)Hexyl-5-(3-aminophenyl)]-Benzylmethylene}-β-D-ribopyranosyl]uracil(119)

In another embodiment of the present invention the Spiro annulatednucleoside of general Formula I is useful as potential anti-cancer andanti-viral agents.

In another embodiment of the present invention a process for thepreparation of Spiro annulated nucleoside of general Formula I, whereinthe said process comprising the steps of;

-   a) preparing solution of diyne and alkyne in mole ratio ranging    between 1:1 to 1:3 in a solvent followed by degassing of solution    with dry argon;-   b) adding a catalyst in mole ratio ranging between 0.02 to 0.05 into    the degassed solution as obtained in step (a) followed by heating at    temperature in the range of 70° C.-90° C. for a period in the range    of 6 h-12 h;-   c) cooling the solution as obtained in step (b) to room temperature    ranging between 25° C.-30° C. followed by solvent evaporation and    purification to obtain spiroannulated nucleoside.

In another embodiment of the present invention a process for thepreparation of Spiro annulated nucleoside of general Formula I, whereinthe said process comprising the steps of;

-   a. charging of diyne in a solvent in a sealed tube followed by    degassing with alkyne;-   b. adding a catalyst into the solution as obtained in step (a);-   c. cooling the reaction mixture as obtained in step (b) at    temperature ranging between −80° C.-−70° C. followed by bubbling of    alkyne for a period ranging between 25 min. to 60 min and sealing of    tube;-   d. transferring the sealed tube as obtained in step (c) in a steal    bomb and heating at temperature ranging between 70° C.-90° C. for a    period ranging between 6 h-12 h followed by cooling to room    temperature ranging between 25° C.-30° C.;-   e. evaporating the solvent from reaction mixture as obtained in    step (d) and purification to obtain spiroannulated nucleoside.

In another embodiment of the present invention a process, whereinpenultimate nucleoside diynes used in step (a) is selected from thegroup consisting of furanoside nucleoside, pyranoside nucleoside(1-[3-C-phenylethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil),(1-[3-C-(1-octynyl)-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil),(1[3-C-phenylethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil),1-[3-C-Propynyl/Phenylpropynyl/^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]5-flurouracil),(1[3-C-Propynyl/Phenylpropynyl/^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]5-flurouracil).

In another embodiment of the present invention a process, wherein thesymmetrical and unsymmetrical alkynes used in step (a) and also in step(c) is selected from the group consisting of acetylene (CH≡CH), terminalalkyne of the formula R—C≡CH where R is selected from C1-C30 straight orbranched alkyl groups optionally substituted with halo, —OH, —OAc,—CH₂OH; a phenyl group further optionally substituted with lower alkyl,halo, —OH, —OAc; diacetate of 2-butyne-1,4-diol, an alkyne of theformula R″—C≡C—R″′ where R″ and R″′ are selected from either straight orbranched chain alkyl group, —CH₂OH, —CH₂OAc, —COOH, —COOAc,TMS,N-propyne pthalimide.

In another embodiment of the present invention 1,3-dihydroisobenzofuranis appended on the sugar moiety of the nucleoside via [2+2+2]cyclotrimerization reaction.

In another embodiment of the present invention isochroman[3,4-dihydro-1H-benzo[c]pyran] is appended on the sugar moiety of thenucleoside via [2+2+2] cyclotrimerization reaction.

In another embodiment of the present invention the spiroannulation ofthe nucleoside diyne with the symmetrical and unsymmetrical alkyne takesplace at C-3 of the furanoside ring.

In another embodiment of the present invention the spiroannulation ofthe nucleoside diyne with the symmetrical and unsymmetrical alkyne takesplace at C-3 of the pyranoside ring.

In another embodiment of the present invention catalyst used in step (b)is selected from Wilkinson's catalyst [RhCl(PPh3)3, Cp*RuCl(cod) and[Rh(cod)2]BF4/(R)-BINAP.

In another embodiment of the present invention solvent used in step (a)is selected from the group consisting of toluene, xylene, methanol,ethanol, propanols and mixture thereof.

In another embodiment of the present invention yield of spiroannulatednucleoside is in the range of 71-87%.

BRIEF DESCRIPTION OF DRAWING

Scheme 1. Reagents and Conditions: a) TBAF, THF, rt, 8 h; b) PivCl,DMAP, CH₂Cl₂, rt, 6 h; c) i. 60% AcOH, reflux, 2 h; ii. Ac₂O, Et₃N,DMAP, CH₂Cl₂, rt, 1 h; d) uracil/5-flurouracil/thymineN,O-bis(trimethylsilyl)-acetamide (BSA), TMSOTf, CH₃CN, 50° C., 2 h; e)NaOMe, MeOH, rt, 20 min.

Scheme 2: Reagents and Conditions: a) n-BuMgCl, phenylacetylene/1-octyne, 0° C. 1 h; b) NaH, THF, 0° C.-rt, 3 h; c) TBAF, THF,rt, 8 h; d) PivCl, DMAP, CH₂Cl₂, 0° C.-rt, 6 h; e) i. 60% AcOH, reflux,2 h; ii. Ac₂O, Et₃N, DMAP, CH₂Cl₂, rt, 1 h; f)uracil/5-flurouracil/thymine N,O-bis(trimethylsilyl)-acetamide (BSA),TMSOTf, CH₃CN, 50° C., 2 h; g) NaOMe, MeOH, rt, 20 min.

Scheme 3: Reagents and Conditions: a) Zn, Propargyl/substitutedpropargyl bromide, 0° C. 1 h; b) NaH, THF, 0° C.-rt, 3 h; c) TBAF, THF,rt, 8 h; d) PivCl, DMAP, CH₂Cl₂, 0° C.-rt, 6 h; e) i. 60% AcOH, reflux,2 h; ii. Ac₂O, Et₃N, DMAP, CH₂Cl₂, rt, 1 h; f) uracil,N,O-bis(trimethylsilyl)-acetamide (BSA), TMSOTf (trimethylsilyltrifluoromethanesulphonate), CH₃CN, 50° C., 2 h; g) NaOMe, MeOH, rt, 20min.

DETAILED DESCRIPTION

The invention will now be described in detail in connection with certainpreferred and optional embodiments, so that various aspects thereof maybe more fully understood and appreciated and briefly described asfollows.

The term “nucleoside” used herein refers to glycosylamines consisting ofa nucleobase (often referred to as simply base) bound to a ribose ordeoxyribose sugar via a beta-glycosidic linkage.

The term “[2+2+2]-cyclotrimerization” or ‘cyclotrimerization” or“spiroannulation” extensively refer in the specification tointermolecular cycloaddition reaction between the penultimate nucleosidediynes with various symmetrical or unsymmetrical alkynes.

The present invention describes modification of the sugar backbone inthe nucleoside for developing a library of small molecules that maycontrol genetic disorders or infections.

Considering the fact that the benzenoid unit is ubiquitous in naturalproducts as well as in medicinal compounds, it is foreseen that throughjudicious retrosynthetic planning and employing[2+2+2]-cyclotrimerisation, a rapid access to a collection ofspiroannulated nucleosides can be made possible. Further, consideringthe prevalence of the isochroman or dihydroisobenzofuran structural unitin many of the naturally occurring substances, and drug candidates, thepresent invention provides a process, wherein, the said structural unitsare appended on the sugar template of the nucleoside by employing alkynecyclotrimerisation.

Thus in an embodiment, the present invention discloses the synthesis ofenantiopure tricyclic systems comprising of isochroman ordihydroisobenzofuran units integrated with sugar templates. The bicyclicring construction on the sugar moiety in the nucleoside is effected viaintermolecular [2+2+2] alkyne cyclotrimerization reaction of nucleosidediynes at the final stage thereby providing a provision to alter thefunctional groups on the newly formed aromatic rings. By selecting therepresentative diyne products, various tricyclic nucleosides aresynthesized by simple synthetic manipulations.

The process of the present invention comprises intermolecular [2+2+2]cyclotrimerization reaction of symmetrical or unsymmetrical alkynes withthe nucleoside diynes to obtain enantiopure tricyclic systems of thegeneral Formula I;

where, R (in the base) is selected from H, C₁-C₄ alkyl, halogen, OR, NHR(R═H, COCH₃, COO^(t)Bu); Q=H with the proviso that C—N double bond isabsent, C—Z double bond is present and Z is O; Z is NH₂ with the provisothat C—Z double bond is absent, Q≠H; Z is O with the proviso that C—Ndouble bond is absent;

A and A′ are selected from H, lower alkyl, —OH, —OAc CH₂OH, —CH₂OAc,—CH₂OPiv, —CH₂OTBS; m and n are integers 0,1

A″ and A′″ are selected from 1,3-dihydroisobenzofuran (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b),

where R, R′, R″ are selected from H, —OH, halo group, —CH₂OH, —CH₂OAc,—COOH, —COOMe, C1-C30 straight or branched alkyl group, optionallysubstituted with halogen or —OH or —NH₂ or —NPhth; phenyl groupoptionally substituted with halogen, amino, nitro, C1-C6 alkyl;

with the proviso that when n=1[i.e(CH₂)n=1] and where m=0[i.e(CH₂)m=0],A′″ is absent and A″ is 1,3-dihydro isobenzofuran (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), directlyannulated at C-3, A and A′ are selected from H, lower alkyl, —OH, —OAc,—CH₂OH—CH₂OAc, —CH₂OPiv, —CH₂OTBS,; and R, R′ and R″ in 1,3-dihydroisobenzofuran (1a) or isochroman [3,4-dihydro-1H-benzo[c]pyran]represented by the formula (1b) are selected from H, —OH, halo group,—CH₂OH, —CH₂OAc, —COOH, —COOMe, C1-C30 straight or branched alkyl group,optionally substituted with halogen or —OH or —NH₂ or —NPhth; phenylgroup optionally substituted with halogen, amino, nitro, C1-C6 alkyl; R(in the base) is selected from H, C1-C4 alkyl, halogen; Q=H with theproviso that C—N double bond ( . . . . ) is absent, C—Z double bond ispresent and Z is O; Z is NH₂ with the proviso that C—Z double bond isabsent, Q≠H; Z is O with the proviso that C—N double bond is absent;

with the proviso that when both n=1 and m=1, A″ is absent and A″′ isselected from 1,3-dihydroisobenzofuran of formula (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), A and A′are selected from H, lower alkyl, —OH, —OAc, —CH₂OH, —CH₂OAc; R, R′ andR″ in 1,3-dihydroisobenzofuran of formula (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b) areselected from H, —OH, —OAc, halo group, —CH₂OH, —CH₂OAc, —COOH, —COOMe,C 1-C30 straight or branched alkyl group, optionally substituted withhalogen or —OH or —NH₂ or —NPhth; phenyl group optionally substitutedwith halogen, amino, nitro, C1-C6 alkyl; R (in the base) is selectedfrom H, C1-C4 alkyl, halogen; Q=H with the proviso that C—N double bondis absent, C—Z double bond is present and Z is O; Z is NH₂ with with theproviso that C—Z double bond is absent, Q≠H; Z is O with the provisothat C—N double bond is absent;

with the proviso that both A and A″ can form together1,3-dihydroisobenzofuran (1a) where R, R′ and R″, are selected from H,—OH, halo group, —CH₂OH, —CH₂OAc, —COOH, —COOMe, C1-C30 straight orbranched alkyl group, optionally substituted with halogen or —OH or —NH₂or —NPhth; phenyl group optionally substituted with halogen, amino,nitro, C1-C6 alkyl when m=0[i.e(CH₂)m=0], A″′ is absent and A′ isselected from H, lower alkyl, —OH, —OAc, —CH₂OH, —CH₂OAc, —CH₂OMe,—CH₂OEt, phenyl optionally substituted with halogen, amino, nitro, C1-C6alkyl.

The symmetrical and unsymmetrical alkynes are selected from the groupcomprising of acetylene (CH≡CH), terminal alkyne of the formula R—C≡CHwhere R is selected from C1-C30 straight or branched alkyl groupsoptionally substituted with halo, —OH, —OAc, —CH₂OH; a phenyl groupfurther optionally substituted with lower alkyl, halo, —OH, —OAc;diacetate of 2-butyne-1,4-diol, an alkyne of the formula R″—C≡C—R″′where R″ and R″′ are selected from either straight or branched chainalkyl group, —CH₂OH, —CH₂OAc, —COOH, —COOAc, TMS,N-propyne pthalimide.

In a preferred embodiment, the present invention disclosesspiroannulation on the sugar template of the penultimate nucleosidediyne with various symmetrical and unsymmetrical alkynes.

Accordingly, in one of the preferred embodiment, the process of thepresent invention comprises intermolecular [2+2+2]-cyclotrimerization ofthe furanoside diyne 1-3, as suitable precursors with symmetrical andunsymmetrical alkynes in the presence of Wilkinson's catalyst[RhCl(PPh₃)₃].

In another preferred embodiment, the process of the present inventioncomprises intermolecular [2+2+2] cyclotrimerization of thepyranosidediyne 4-6, as suitable precursors with symmetrical andunsymmetrical alkynes in the presence of Wilkinson's catalyst[RhCl(PPh₃)₃].

The key furanoside and pyranoside diynes 1-6 employed in the presentinvention, wherein the critical spiroannulation is executed at the finalstage, are synthesized from the known intermediate 7.

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil (01):

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]thymine (02):

1-[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]5-flurouracil(03):

1[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil (04):

1[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]thymine (05):

1[3-C-Ethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]5-flurouracil (06):

Accordingly, compound 7 is converted to the corresponding pivolatederivative 9 by deprotection of the TBS ether using TBAF in THF andreprotection of the resulting alcohol 8 using pivoloyl chloride andEt₃N. Selective acetonide hydrolysis of compound 9 followed byacetylation (Ac₂O/Et₃N) gave a 1:1 anomeric mixture of diacetates 10.The glycosidation of the anomeric mixture 10 is carried out undermodified Vorbrüggen conditions employing uracil, thymine and5-flurouracil preferably as glycosyl to afford the protected nucleosides11-13, respectively. The protected nucleosides 11-13 are then subjectedto Zemplen's deacetylation to yield furanose nucleosides 1-3, which havethe key diyne unit for the cycloisomerization reactions.

Further, synthesis of the pyranosyl nucleoside precursors 4-6 involvesinitially deprotection of 9 using acetic acid followed by theperacetylation employing acetic anhydride and Et3N in dichloromethane toafford the corresponding β-anomer 14 exclusively. The N-glycosidation of14 with pyrimidine base selected from uracil, 5-flurouracil and thymineunder modified Vorbrüggen conditions followed by deacetylation of theresulting compounds 15-17 gave the pyranose nucleosides 4-6. The processfor the synthesis of diynes 1-6 is schematically given in Scheme 1.

Thus according to the preferred embodiment, the furanoside diynes 1-3and the pyranoside diyne 4-6 obtained above are subjected totrimerization with various symmetrical and unsymmetrical alkynes toobtain a library of small molecules of modified nucleosides.

The generalized reaction of the intermolecular[2+2+2]-cyclotrimerization of the nucleoside diynes 1-6 with varioussymmetrical or unsymmetrical alkynesis represented below:

In an embodiment, the trimerization reaction of diynes 1-6 is carriedout effectively with acetylene (R═R′═H) in presence of Wilkinson'scatalyst in presence of solvent selected from aromatic hydrocarbons,lower alcohols at 80° C. in a sealed tube for 6-8 hours to obtain thecorresponding products 18-23 respectively.

The aromatic hydrocarbons are selected from toluene, xylene, etc and thelower alcohols are selected from methanol, ethanol, propanols etc.

In another embodiment, the diynes 1-6 are reacted with the diacetate of2-butyne-1,4-diol to obtain the corresponding isobenzofurannulatednucleosides 24-29 in good yields.

In yet another embodiment, the cyclotrimerization reactions of diynes1-6 is carried out with 1-heptyne to yield the regiomeric mixtures30-35.

The scope of the cyclotrimerisation reaction of diynes 1-6 is givenbelow in Chart 1.

CHART 1 Scope of the cyclotrimerization reaction of diynes 1-6

18 R = R′ = H (79%) 19 R = R′ = H (77%) 20 R = R′ = H (75%) 24 R = R′ =CH₂OAc (83%) 25 R = R′ = CH₂OAc (85%) 26 R = R′ = CH₂OAc (82%) 30 R orR′ = C₅H₁₁ (80%) 31 R or R′ = C₅H₁₁ (81%) 32 R or R′ = C₅H₁₁ (79%)

21 R = R′ = H (71%) 22 R = R′ = H (69%) 23 R = R′ = H (73%) 27 R = R′ =CH₂OAc (78%) 28 R = R′ = CH₂OAc (74%) 29 R = R′ = CH₂OAc (80%) 33 R orR′ = C₅H₁₁ (81%) 34 R or R′ = C₅H₁₁ (86%) 35 R or R′ = C₅H₁₁ (79%)

In another embodiment, cyclotrimerisation of diynes 1-6 withbis-(trimethylsilyl)acetylene and dimethyl acetylene dicarboxylate asrepresentative symmetric disubstituted alkynes yielded, however,self-dimerized products or a complex mixture.

A similar lack of regioselectivity was observed when other catalystssuch as Cp*RuCl(cod) and [Rh(cod)₂]BF₄/(R)-BINAP were employed.

The regioselectivity is the critical limitation with the[2+2+2]-cyclotrimerisation reactions, which has been addressed to someextent in the present invention by the placement of a substituent on anyof the alkynes of the diyne unit.

In an embodiment of the present invention, cyclotrimerisation of diynes36-38 with the terminal alkynes is carried out to determine theregioselectivity.

Accordingly, ketone 39 is reacted with alkynylmagnesium chloride(prepared by Grignard exchange between the corresponding alkyne andn-butylmagnesium chloride) followed by propargylation of 3°-hydroxyl inthe resulting alkynols 40, 41 to obtain the diyne intermediates 42 and43 respectively. The compounds 42 and 43 are then converted to thecorresponding pivolate derivatives 46 and 47 followed by a sequence ofTBS deprotection and pivoloylation reactions. Subsequent acetonidehydrolysis of 46 and 47, acetylation (Ac₂O/Et₃N) and the N-glycosidationwith uracil, and final saponification under Zemplen's conditions yieldedthe furanose nucleosides 36 and 37. Further, deprotection of 42 usingacetic acid followed by the peracetylation, N-glycosidation with uraciland deacetylation yielded pyranosyl nucleoside 38.

1-[3-C-Phenylethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil(36):

1-[3-C-(1-Octynyl)-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil (37):

1[3-C-Phenylethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil (38):

Thus in another preferred embodiment, the furanoside diynes 36-37 andpyranoside diyne 38 are subjected to cyclotrimerisation reaction inpresence of catalyst Cp*RuCl(cod) and in presence of DCE-ethanol (5:1)at room temperature yielded isobenzofurannulated products

with excellent regioselectivity. The generalized reaction is givenbelow:

Thus in an embodiment, cyclotrimerisation of diyne 36 (where R=Ph) withvarious terminal alkynes yielded compounds 54-59 in good yield and withexcellent regioselectivity.

In another embodiment, cyclotrimerisation of diyne 37 (where R═C₆H₁₃)with various terminal alkynes yielded compounds 60-63 in good yield andwith excellent regioselectivity.

In yet another embodiment, cyclotrimerisation of diyne 38 with phenylacetylene gave a 7:1 regiomeric mixture, with the 1,3-product being themajor one. The diynes 36 and 37 on reaction with phenyl acetyleneyielded the 1,3-product exclusively.

The amine group present in the products 58, 59 and the chloro functionalgroup present in the products and 57, 63, and 67 provide a suitablehandle for further diversification in the present invention.

The scope of the cyclotrimerisation reaction of diynes 36-38 is givenbelow in chart 2.

CHART 2 Scope of the cyclotrimerization reaction of diynes 36-38

54 R′ = —Ph (85%) 60 R′ = —Ph (78%) 64 R′ = —Ph (83%, dr = 7:1) 55 R′ =—^(n)C₆H₁₃ (78%) 61 R′ = —^(n)C₆H₁₃ (74%) 65 R′ = —^(n)C₆H₁₃ (77%) 56 R′= —^(n)C₂₁H₄₃ (87%) 62 R′ = —^(n)C₂₁H₃ (73%) 66 R′ = —^(n)C₂₁H₄₃ (81%)57 R′ = —(CH₂)₃Cl (83%) 63 R′ = —(CH₂)₃Cl (78%) 67 R′ = —(CH₂)₃Cl (79%)58 R′ = —CH₂NPht (80%) 59 R′ = m-(Ar—NH₂) (85%)

In yet another preferred embodiment, the present invention comprises thesynthesis of Spiro-benzo-pyrannulated nucleosides. This includesconverting ketone 39 to diyne intermediates as depicted in Scheme 3below:

According to the Scheme 4, ketone 39 is converted to alkynols 68 byapplying Barbier reaction with halo-alkyne e.g. propargyl bromide andsubstituted propargyl bromides (R═H, C₆H₁₃— and Ph-). Subsequentpropargylation of 3°-hydroxyl in the resulting alkynols 68 gave thediyne intermediates 69. The preparation of furanoside diynes involvedconverting the intermediates 69 to the corresponding pivolatederivatives 71 following a sequence of TBS deprotection andpivoloylation reactions. Subsequent acetonide hydrolysis of 71,acetylation (Ac₂O/Et₃N) and the N-glycosidation with uracil, and finalsaponification under Zemplen's conditions afforded the furanosenucleosides 77. Synthesis of the pyranosyl nucleoside 74 includes theglobal deprotection of 69 using acetic acid followed by theperacetylation, N-glycosidation with uracil and deacetylation.

In another preferred embodiment, the furanoside diyne 74 and pyranosidediyne 77 are subjected to [2+2+2]-cyclotrimerisation with variousterminal diynes to obtain the desired spiroannulated nucleosides. Thegeneralized spiroannulation is depicted below;

In an embodiment, the furanoside diyne 77a (R═H) is cyclotrimerized withvarious terminal alkynes (where R═H) to obtain the products 78-84 ingood yields.

In another embodiment, the furanosidediyne 77b (R=Ph) is cyclotrimerizedwith various terminal alkynes (where R═H) to obtain the products 85-91in good yields.

In yet another embodiment, the furanoside diyne 77c (R═^(n)C₆H₁₃) iscyclotrimerized with various terminal alkynes (where R═H) to obtain theproducts 92-98 in good yields.

In another embodiment, the pyranosidediyne 74a (R═H) is cyclotrimerizedwith various terminal alkynes (where R═H) to obtain the products 99-105in good yields.

In yet another embodiment, the pyranoside diyne 74b (R=Ph) iscyclotrimerized with various terminal alkynes (where R═H) to obtain theproducts 106-112 in good yields.

In yet another embodiment, the pyranoside diyne 74c (R═^(n)C₆H₁₃) iscyclotrimerized with various terminal alkynes (where R═H) to obtain theproducts 113-119 in good yields.

1-[3-C-Propynyl -3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil (74a):

1-[3-C-Phenylpropynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]thymine(74 b):

1-[3-C-^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]5-flurouracil (74c):

1[3-C-Propynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil (77a):

1[3-C-Phenylpropynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]thymine (77b):

1[3-C-^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]5-flurouracil(77c):

The scope of cyclotrimerization of diynes 74 and 77 is given below inChart 3

CHART 3 Scope of cyclotrimerization reaction of the diynes 74 and 77

78 R′ = H 85 R′ = H 92 R' = H 79 R′ = —Ph 86 R′ = —Ph 93 R′ = —Ph 80 R′= —^(n)C₆H₁₃ 87 R′ = —^(n)C₆H₁₃ 94 R′ = —^(n)C₆H₁₃ 81 R′ = —^(n)C₂₁H₄₃88 R′ = —^(n)C₂₁H₄₃ 95 R′ = —^(n)C₂₁H₄₃ 82 R′ = —(CH₂)₃Cl 89 R′ =—(CH₂)₃Cl 96 R′ = —(CH₂)₃Cl 83 R′ = —CH₂NPht 90 R′ = —CH₂NPht 97 R′ =—CH₂NPht 84 R′ = m-(Ar—NH₂) 91 R′ = m-(Ar—NH₂) 98 R′ = m-(Ar—NH₂)

99 R′ = H 106 R′ = H 113 R' = H 100 R′ = —Ph 107 R′ = —Ph 114 R′ = —Ph101 R′ = —^(n)C₆H₁₃ 108 R′ = —^(n)C₆H₁₃ 115 R′ = —^(n)C₆H₁₃ 102 R′ =—^(n)C₂₁H₄₃ 109 R′ = —^(n)C₂₁H₄₃ 116 R′ = —^(n)C₂₁H₄₃ 103 R′ = —(CH₂)₃Cl110 R′ = —(CH₂)₃Cl 117 R′ = —(CH₂)₃Cl 104 R′ = —CH₂NPht 111 R′ =—CH₂NPht 118 R′ = —CH₂NPht 105 R′ = m-(Ar—NH₂) 112 R′ = m-(Ar—NH₂) 119R′ = m-(Ar—NH₂)

In an embodiment of the present invention, it is possible to develop alibrary of modified sugar template on the nucleoside by means of[2+2+2]-cyclotrimerisation as the last step of the process. Further, inthe present invention by simple synthetic manipulations, D-xylose ismodified into eleven different modified nucleosides having the diyneunit. The present strategy is further characterized by flexibility atthe final stages and synthesis with a complete redox economy.

The present invention is illustrated herein below with examples, whichare illustrative only and should not be construed to limit the scope ofthe present invention in any manner.

EXPERIMENTAL

General Methods: Air and/or moisture sensitive reactions were carriedout in anhydrous solvents under an argon atmosphere in oven-driedglassware. All anhydrous solvents were distilled prior to use: Toluenefrom Na and benzophenone; CH₂Cl₂ and DMF from CaH₂; MeOH and EtOH fromMg cake. Commercial reagents were used without purification. Columnchromatography was carried out by using Spectrochem silica gel (100-200mesh). Optical rotations were determined on a Jasco DIP-370 digitalpolarimeter. Specific optical rotations [α]_(D) ²⁵ are given in 10⁻¹ degcm² g⁻¹. ¹H and ¹³C NMR spectroscopy measurements were carried out onBruker AC 200 MHz or Bruker DRX 400 MHz spectrometers, and TMS was usedas internal standard. The ¹H and ¹³C NMR chemical shifts are reported inppm downfield from tetramethylsilane and the coupling constants (J) arereported in Hertz (Hz). The following abbreviations are used todesignate signal multiplicity: s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet, br=broad. The multiplicity of the ¹³C NMRsignals was assigned with the help of DEPT spectra and the termss=singlet, d=doublet, t=triplet and q=quartet represent C (quaternary),CH, CH₂ and CH₃ respectively. Mass spectroscopy was carried out on anAPI QStar Pulsar (Hybrid Quadrupole-TOF LC/MS/MS) spectrometer.Elemental analysis data were obtained on a Thermo Finnigan Flash EA 1112Series CHNS Analyzer.

Representative Procedures for the [2+2+2]-Cyclotrimerization Reactionsof Diynes:

Procedure A: A solution of diyne 1 (0.5 mmol) and alkyne (1.5 mmol) in4:1 toluene/ethanol (12 mL) was degassed with dry argon for 20 min. Tothis, Wilkinson's catalyst [RhCl(PPh₃)₃] (0.03 mmol) was added, and themixture was heated at 80° C. for 6 h and then allowed to cool to roomtemperature. The solvent evaporated under reduced pressure. The residuewas purified by silica gel chromatography to procure thecyclotrimerization product.

Procedure B: A solution of diyne 1 (0.5 mmol) in toluene/ethanol (12 and3 mL, respectively) in a sealed tube was degassed with dry alkyne for 20min; then, Wilkinson's catalyst [RhCl(PPh₃)₃] (0.03 mmol) was introducedinto the mixture. The reaction mixture was cooled to −78° C., and alkynegas was condensed by continuous bubbling for 25 min. and the tube sealedby fusion. The sealed tube was transferred into steel bomb, heated at80° C. for 6 h. After cooling to room temperature, the tube was brokenand the mixture was transferred into a round-bottom flask andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (ethyl acetate in petroleum ether) to afford thecyclotrimerized product.

Procedure C: A solution of diyne 1 (0.5 mmol) and alkyne (0.5 mmol) inDCE (5 mL) was degassed with dry argon for 20 min. To this, Cp*RuCl(cod)catalyst (0.03 mmol) was added, and the mixture was stirred for 4-6 h at25-30° C. The solvent evaporated under reduced pressure. The residue waspurified by silica gel chromatography to procure the cyclotrimerizationproduct.

EXAMPLES Example 1

1-[3-C,3-O-(o-Phenylenemethylene)-β-D-ribofuranosyl]uracil (18):Following procedure B, using diyne 1 (100 mg, 0.33 mmol) and acetylenegas were used to get a product 18 (85.7 mg, 79% yield) as a White solid,mp: 234-236° C.; [α]_(D) ²⁵+14.3 (c 0.3, MeOH); IR (CHCl₃): 3630, 3371,3018, 1728, 1522, 1421, 1375, 1216, 1120, 1048, 975, 757 cm⁻¹; ¹H NMR(CDCl₃:CD₃OD; 3:1, 500 MHz): δ 3.38 (dd, J=1.2, 12.1 Hz, 1H), 3.64 (dd,J=2.8, 12.1 Hz, 1H), 4.07 (dd, J=1.2, 2.8 Hz, 1H), 4.45 (d, J=8.2 Hz,1H), 5.03 (d, J=12.7 Hz, 1H), 5.05 (d, J=12.7 Hz, 1H), 5.60 (d, J=8.2Hz, 1H), 5.91 (d, J=8.2 Hz, 1H), 7.08-7.10 (m, 1H), 7.17-7.19 (m, 2H),7.62 (dd, J=1.9, 6.8 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H); ¹³C NMR(CDCl₃:CD₃OD; 3:1, 125 MHz): δ 60.4 (t), 72.2 (t), 78.1 (d), 86.0 (d),87.7 (d), 94.8 (s), 102.2 (d), 120.6 (d), 123.1 (d), 127.6 (d), 128.6(d), 134.9 (s), 140.9 (s), 142.0 (d), 151.3 (s), 164.3 (s) ppm; ESI-MS(m/z): 333.4 (18%, [M+H]⁺), 355.3 (100%, [M+Na]⁺), 371.3 (32%, [M+K]⁺);Anal. Calcd for C₁₆H₁₆N₂O₆: C, 57.83; H, 5.85; N, 8.43%; Found: C,57.51; H, 5.99; N, 8.21%.

Example 2

1-[3-C,3-O-(o-phenylenemethylene)-β-D-ribopyranosyl]uracil (21): Byfollowing procedure B, cycloaddition of the diyne 4 (100 mg, 0.55 mmol)with acetylene gave 21 (77 mg, 71% yield) as a White solid, mp: 138-140°C.; [α]_(D) ²⁵+56.5 (c 0.4, MeOH); IR (nujol) v: 3393, 3018, 2961, 2854,1679, 1459, 1377, 1243, 1062 cm⁻¹; ¹H NMR (CD₃OD, 400 MHz): δ 3.85 (t,J=10.8 Hz, 1H), 3.94 (dd, J=5.4, 10.8 Hz, 1H), 4.03 (dd, J 5.4, 10.8 Hz,1H), 4.06 (d, J=9.5 Hz, 1H), 5.22 (d, J=11.8 Hz, 1H), 5.27 (d, J=11.8Hz, 1H), 5.73 (d, J=8.1 Hz, 1H), 5.86 (d, J=9.5 Hz, 1H), 7.25 (dd,J=6.1, 1.55 Hz, 1H), 7.30-7.35 (m, 2H), 7.38-7.40 (m, 1H), 7.79 (d,J=8.1 Hz, 1H);¹³C NMR (CD₃OD, 100 MHz): d 68.8 (t), 71.4 (d), 72.7 (d),75.8 (t), 83.7 (d), 93.9 (s), 103.2 (d), 121.8 (d), 122.3 (d), 128.6(d), 129.4 (d), 139.5 (s), 142.9 (d), 143.0 (s), 152.9 (s), 166.1 (s)ppm; ESI-MS (m/z): 333.60 (19.12%, [M+1]⁺), 355.60 (100%, [M+Na]⁺),371.57 (11.03%, [M+K]⁺); Anal. Calcd for C₁₆H₁₆N₂O₆: C, 57.83; H, 4.85;N, 8.43%; Found: C, 57.95; H, 4.98; N, 8.56%.

Example 3

1-[3-C,3-O-{o-(3,4-acetyloxymethyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(24): General procedure A was followed. Diyne 1 (100 mg, 0.33 mmol) and1,4-Diacetoxy-2-butyne (0.24 mL, 1.63 mmol) were used to afford 24 (129mg, 83% yield) as a White solid, mp: 181-183° C.; [α]_(D) ²⁵+25.0 (c0.5, MeOH); IR (CHCl₃) v: 3683, 3304, 3019, 2400, 1749, 1600, 1422,1478, 1424, 1372, 1216, 1030, 928 cm⁻¹; ¹H-NMR (CDCl₃:CD₃OD; 3:1, 500MHz): δ 2.02 (s, 3H), 2.04 (s, 3H), 3.45 (dd, J=1.0, 11.8 Hz, 1H), 3.77(dd, J=2.9, 12.0 Hz, 1H), 4.16 (dd, J=1.1, 2.7 Hz, 1H), 4.57 (d, J=8.2Hz, 1H), 5.11 (d, J=12.7 Hz, 1H), 5.13 (d, J=2.4, 12.7 Hz, 1H),5.15-5.17 (m, 4H), 5.16 (d, J=12.4 Hz, 1H), 5.71 (d, J=8.1 Hz, 1H), 5.95(d, J=8.2 Hz, 1H), 7.78 (s, 1H), 8.09 (d, J=8.2 Hz, 1H); ¹³C NMR(CDCl₃:CD₃OD; 3:1, 125 MHz): δ 20.8 (q, 2C) 60.6 (t), 63.4 (t), 64.1(t), 72.3 (t), 78.2 (d), 86.0 (d), 88.3 (d), 95.1 (s), 102.7 (d), 122.1(d), 125.5 (d), 134.1 (s), 135.7 (s), 135.8 (s), 142.0 (s), 142.1 (d),151.3 (s), 164.0 (s), 170.9 (s), 171.3 (s) ppm; ESI-MS (m/z): 477.4(5.3%, [M+H]⁺), 499.3 (100%, [M+Na]⁺), 515.5 (3.5%, [M+K]⁺); Anal. Calcdfor C₂₂H₂₄N₂O₁₀: C, 55.46; H, 5.08; N, 5.88%; Found: C, 55.30; H, 5.21;N, 5.93%.

Example 4

1-[3-C,3-O-{o-(3,4-acetyloxymethyl)phenylenemethylene}-β-D-ribopyranosyl]uracil(27): Cycloaddition of diyne 4 (130 mg, 0.42 mmol) and1,4-Diacetoxy-2-butyne (0.32 mL, 2.12 mmol) following procedure B gave27 (164 mg, 81% yield) as a Liquid, [α]_(D) ²⁵+15.9 (c 0.4, MeOH); IR(CHCl₃) v: 3687, 3650, 3567, 3019, 2930, 2400, 1732, 1693, 1612, 1517,1474, 1423, 1386, 1216, 1075, 1028, 961, 928 cm⁻¹; ¹H NMR (CDCl₃:CD₃OD;3:1, 400 MHz): δ 1.87 (s, 6H), 3.62 (t, J=12.5 Hz, 2H), 3.67 (d, J=9.4Hz, 1H), 3.75 (dd, J=1.8, 5.3 Hz, 1H), 3.78 (dd, J=1.8, 5.3 Hz, 1H),4.99 (s, 2H), 5.00 (s, 2H), 5.52 (d, J=8.1 Hz, 1H), 5.59 (d, J=9.4 Hz,1H), 7.08 (s, 1H), 7.12 (s, 1H), 7.33 (d, J=8.1 Hz, 1H); ¹³C NMR(CDCl₃:CD₃OD; 3:1, 100 MHz): δ 20.2 (q), 20.3 (q), 63.3 (t) 63.7 (t),67.2 (t), 69.7 (d), 71.5 (d), 74.2 (t), 82.0 (d), 92.1 (s), 102.1 (d),121.9 (d), 122.1 (d), 133.7 (s), 134.9 (s), 138.1 (s), 140.4 (d), 141.8(s), 151.0 (s), 163.9 (s), 170.9 (s), 171.1 (s) ppm; ESI-MS (m/z): 477.9(0.8%, [M+H]⁺), 499.9 (100%, [M+Na]⁺), 515.9 (1.3%, [M+K]⁻); Anal. Calcdfor C₂₂H₂₄N₂O₁₀: C, 55.46; H, 5.88; N, 5.88%; Found: C, 55.39; H, 5.96;N, 5.78%.

Example 5

1-[3-C,3-O-{o-(3/4-^(n)pentyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(30): General procedure A was followed. Diyne 1 (120 mg, 0.39 mmol) and1-heptyne (0.26 mL, 1.96 mmol) were used to afford 30 (126 mg, 80%yield) as a White solid, mp: 241-143° C.; IR (CHCl₃) v: 3683, 3019,2400, 1695, 1522, 1476, 1424, 1416, 1021, 908 cm⁻¹; ¹H NMR (CDCl₃:CD₃OD;3:1, 400 MHz): δ 0.85 (t, J=6.5 Hz, 3H), 1.27-1.29 (m, 6H), 1.56 (br.s,3H), 2.57 (dd, J=7.6, 15.4 Hz, 2H), 3.54 (d, J=12.1 Hz, 1H), 3.76 (dd,J=3.0, 12.1 Hz, 1H), 4.18 (m, 1H), 4.57 (t, J=8.5 Hz, 1H), 5.12 (d,J=12.6 Hz, 1H), 5.16 (d, J=12.6 Hz, 1H), 5.72 (d, J=8.1 Hz, 1H), 6.01(d, J=8.1 Hz, 1H), 7.03-7.15 (m, 2H), 7.56-7.64 (m, 1H), 8.18 (dd,J=1.3, 8.2 Hz, 1H); ¹³C NMR (CDCl₃:CD₃OD; 3:1, 100 MHz): δ 13.6 (q),22.2 (t), 31.0 (t), 31.2 (t), 35.5 (t), 35.6 (t), 60.5 (t), 72.1 (t),72.2 (t), 77.3 (s), 77.9 (s), 78.0 (d), 86.0 (2d), 88.0 (d), 88.1 (d),94.7 (s), 102.2 (d), 120.3 (s), 120.4 (d), 122.9 (d), 128.0 (d), 128.9(d), 132.1 (s), 135.0 (s), 138.2 (s), 141.1 (s), 142.1 (2d), 142.7 (d),143.8 (s), 151.3 (s), 164.3 (s) ppm; ESI-MS (m/z): 403.2 (2.4%, [M+H]⁺),425.3 (100%, [M+Na]⁺), 441.2 (4.5%, [M+K]⁺); Anal. Calcd for C₂₁H₂₆N₂O₆:C, 62.67; H, 6.51; N, 6.96%; Found: C, 62.58; H, 6.60; N, 7.03%.

Example 6

1-[3-C,3-O-{o-(3/4-^(n)Pentyl)phenylenemethylene}-β-D-ribofuranosyl]thymine(31): By following procedure A, cycloaddition of the diyne 2 (100 mg,0.31 mmol) with 1-heptyne (0.20 mL, 1.56 mmol) gave 31 (105 mg, 81%yield) as a White solid, mp: 210-212° C.; IR (CHCl₃) v: 3685. 3308,3020, 2400, 1521, 1476, 1423, 1385, 1215, 1100, 1068, 1044, 909, 770,669, 651, 626 cm⁻¹; ¹H NMR (CDCl₃:CD₃OD, 3:1, 400 MHz): δ 0.85 (t, J=6.1Hz, 3H), 1.21-1.29 (m, 4H), 1.57 (br.s, 3H), 1.88 (s, 3H), 2.59 (dd,J=7.6, 15.4 Hz, 2H), 3.52 (d, J=12.1 Hz, 1H), 3.75 (d. J=12.1 Hz, 1H),3.92 (br.s, 1H), 4.61 (t, J=6.8 Hz, 1H), 5.13 (2d, J=12.6 Hz, 2H), 5.94(d, J=7.8 Hz, 1H), 7.02-7.12 (m, 2H), 7.46-7.65 (m, 2H), 7.90 (s, 1H);¹³C NMR (CDCl₃:CD₃OD, 3:1, 100 MHz): δ 11.9 (q), 13.6 (q), 22.2 (t),31.0 (t), 31.2 (t, 2C), 35.5 (t), 35.6 (t), 60.5 (t), 72.1 (t), 72.2(s), 77.2 (s), 77.9 (s), 78.0 (d), 86.0 (2d), 88.0 (d), 88.1 (d), 94.7(s), 102.2 (d), 120.3 (s), 120.4 (d), 122.9 (d), 128.0 (d), 128.9 (d),132.1 (s), 135.0 (s), 138.2 (s), 141.1 (s), 142.1 (2d), 142.7 (s), 143.8(s), 151.3 (s), 164.3 (s) ppm; ESI-MS (m/z): 417.4 (39%, [M+H]⁺), 439.4(100%, [M+Na]⁺), 455.2 (9%, [M+K]⁺); Anal. Calcd for C₂₂H₂₈N₂O₆: C,63.45; H, 6.78; N, 6.73%; Found: C, 63.37; H, 6.83; N, 6.82%.

Example 7

1-[3-C,3-O-{o-(3/4-^(n)pentyl)phenylenemethylene}-β-D-ribopyranosyl]uracil(33): General procedure A was followed. Diyne 4 (120 mg, 0.39 mmol)1-heptyne (0.28 mL, 1.95 mmol) were used to afford a 33 (112 mg, 81%yield) as a Liquid, [α]_(D) ²⁵+31.0 (c 1.7, MeOH); IR (CHCl₃) v: 3672,3565, 3020, 2929, 2400, 1696, 1634, 1539, 1403, 1215, 105, 1029, 929cm⁻¹; ¹H NMR (CDCl₃:CD₃OD; 3:1, 400 MHz): δ 0.82 (t, J =6.4 Hz, 3H),1.22-1.32 (m, 6H), 2.51-2.61 (m, 2H), 3.73-3.70 (m, 2H), 3.85-4.98 (m,2H), 5.17 (d, J=12.1 Hz, 1H), 5.27 (d, J=12.1 Hz, 1H), 5.65 (dt, J=1.9,8.2 Hz, 1H), 5.79 (d, J =8.2 Hz, 1H), 7.00 (d, J=4.0 Hz, 1H), 7.09-7.11(m, 2H), 7.33 (dd, J=1.9, 8.2 Hz, 1H), 9.68 (br.s, 1H); ¹³C NMR(CDCl₃:CD₃OD; 3:1, 100 MHz): δ 13.9 (q), 14.0 (q), 22.3 (t), 22.5 (t),22.6 (t), 29.2 (t), 31.1 (2t), 31.2 (t), 31.5 (t), 31.7 (t), 35.8 (t),35.7 (t), 51.0 (t), 67.8 (t), 70.1 (d), 70.2 (d), 72.6 (d), 72.7 (d),74.9 (t), 77.2 (d), 82.2 (d), 92.0 (s), 102.8 (d), 120.3 (d), 120.4 (d),120.5 (d), 120.7 (d), 128.1 (d), 128.9 (d), 134.4 (s), 137.3 (s), 138.1(s), 139.6 (d), 141.0 (s), 142.7 (s), 143.6 (s), 151.0 (s), 163.0 (s)ppm; ESI-MS (m/z): 403.3 (9%, [M+H]⁺), 425.4 (100%, [M+Na]⁺), 471.5(18%, [M+K]⁺); Anal. Calcd for C₂₁H₂₆N₂O₆: C, 62.67; H, 6.51; N, 6.96%;Found: C, 62.76; H, 6.49; N, 6.82%.

Example 8

1-[3-C,3-O-{o-(2,4-Diphenyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(54): By following procedure C, cycloaddition of the diyne 36 (20 mg,0.052 mmol) with phenyl acetylene (0.005 mL, 0.052 mmol) gave 54 (22 mg,85%) as a White solid, mp: 270-272° C.; [α]_(D) ²⁵+35.0 (c 0.3, CHCl₃);IR (CHCl₃) v: 3020, 2925, 1694, 1526, 1046, 929, 669 cm⁻¹; ¹H NMR(CDCl₃+CD₃OD, 400 MHz): δ 3.29 (dd, J=6.6, 12.1 Hz,1H), 3.35 (dd, J=4.0,12.1 Hz, 1H), 4.20 (dd, J=4.2, 6.4 Hz, 1H), 4.47 (d, J=8.2 Hz, 1H), 5.25(s, 2H), 5.58 (d, J=8.2 Hz, 1H), 6.07 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.2Hz, 1H), 7.36-7.51 (m, 10H), 7.60 (dd, J=1.2, 7.3 Hz, 2H): ¹³C NMR(CDCl₃+CD₃OD, 100 MHz): δ 61.8 (t), 70.4 (t), 76.4 (d), 85.4 (d), 86.6(d), 93.1 (s), 102.7 (d), 118.8 (d), 127.0 (3C, d), 127.8 (d), 128.0(d), 128.3 (d), 128.7 (2C, d), 129.4 (2C, d), 130.0 (s), 130.8 (d),138.5 (s), 139.5 (s), 139.8 (s), 139.8 (d), 142.0 (s), 142.9 (s), 151.0(s), 163.7 (s) ppm; ESI-MS (m/z): 507.02 (70%, [M+Na]⁺), 522.97 (100%,[M+K]⁺); Anal. Calcd for C₂₈H₂₄N₂O₆: C, 69.41; H, 4.99; N, 5.78%; Found:C, 69.30; H, 5.18; N, 5.87%.

Example 9

1-[3-C,3-O-{o-(2-Phenyl-4-^(n)henicosyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(56): General procedure C was followed. Diyne 36 (20 mg, 0.052 mmol) and1-tricosyne (15.9 mg, 0.052 mmol) were used to afford 56 (32 mg, 87%yield) as a Colorless gum, [α]_(D) ²⁵+26.9 (c 0.3, CHCl₃); IR (CHCl₃) v:2924, 2853, 1686, 1466, 1385, 1046, 929, 669 cm⁻¹; ¹H NMR (CDCl₃, 200MHz): δ 0.86 (t, J=6.4 Hz, 3H), 1.24 (m, 36H), 1.52-1.70 (m, 2H), 2.62(t, J=7.7 Hz, 2H), 3.28 (d, J=2.8 Hz, 2H), (m, 3H), 4.10 (t, J=4.5 Hz,1H), 4.50 (dd, J=8.1, 10.5 Hz, 1H), 5.13 (s, 2H), 5.57 (dd, J=1.9, 8.1Hz, 1H), 6.08 (d, J=8.0 Hz, 1H), 6.96 (d, J=1.2 Hz, 1H), 7.04 (d, 8.0Hz, 1H), 7.09 (d, J=1.2 Hz, 1H), 7.41-7.49 (m, 5H); ¹³C NMR (CDCl₃, 100MHz): δ 14.1 (q), 22.7 (t), 29.3 (2C, t), 29.4 (t), 29.6 (t), 29.7 (12C,t), 31.3 (t), 31.9 (t), 35.5 (t), 61.8 (t), 70.3 (t), 77.2 (s), 76.8(d), 84.6 (d), 87.2 (d), 93.7 (s), 103.0 (d), 120.5 (d), 128.3 (d),128.7 (2C, d), 129.3 (2C, d), 131.4 (d), 138.1 (s), 140.0 (s), 140.1(d), 142.5 (s), 144.5 (s), 150.8 (s), 162.9 (s); ESI-MS (m/z): 725.3(80%, [M+Na]), 741.20 (100%, [M+K]⁺); Anal. Calcd for C₄₃H₆₂N₂O₆: C,73.47; H, 8.89; N, 3.99%; Found: C, 73.38; H, 8.97; N, 4.10%.

Example 10

1-[3-C,3-O-{o-(2-phenyl-4-chloropropyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(57): Procedure C was followed. Diyne 36 (20 mg, 0.052 mmol) and1-chloro-4-pentyne (5.33 mmL, 0.052 mmol) were used to afford 57 (21.0mg, 83% yield) as a White solid, mp: 172-174° C.; [α]_(D) ²⁵+12.7 (c0.7, CHCl₃); IR (CHCl₃) v: 669.1, 928.7, 1046.4, 1215.7, 1385.22,1462.17, 1694.16, 2924.8, 3020.1 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 2.08(quin, J=6.8 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 3.23 (dd, J=5.8, 12.1 Hz,1H), 3.30 (dd, J=3.3, 12.1 Hz, 1H), 3.53 (t, J=6.3 Hz, 2H), 3.70 (d,J=8.9 Hz, 1H), 4.11 (t, J=4.5 Hz, 1H), 4.47 (br t, J=7.4 Hz, 1H), 5.12(s, 2H), 5.55 (d, J=8.0 Hz, 1H), 6.06 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.2Hz, 1H), 6.96 (s, 1H), 7.10 (s, 1H), 7.36-7.48 (m, 5H), 9.45 (br s, 1H);¹³C NMR (CDCl₃, 100 MHz): δ 32.22 (t), 33.68 (t), 44.06 (t), 61.89 (t),70.32 (t), 77.20 (s), 84.88 (d), 87.03 (d), 93.53 (s), 102.99 (d),120.63 (d), 128.27 (d), 128.64 (2C, d), 129.36 (2C, d), 129.54 (d),131.42 (d), 138.37 (s), 139.76 (s), 140.02 (d), 142.07 (s), 142.73 (s),150.96 (s), 163.22 (s); ESI-MS (m/z): 507.54 (100%, [M+Na]⁺); Anal.Calcd for C₂₅H₂₅ClN₂O₆: C, 61.92; H, 5.20; Cl, 7.31; N, 5.78%; Found: C,61.82; H, 5.07; N, 5.88%;

Example 11

1-[3-C,3-O-{o-(2-phenyl-4-phthalimidomethyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(58): General procedure C was followed. Diyne 36 (20 mg, 0.052 mmol) andN-propargyl pthalimide (9.4 mg, 0.052 mmol) were used to afford 58 (23.7mg, 80% yield) as a White solid, mp: 196-198° C.; [α]_(D) ²⁵+8.2 (c 1.6,CHCl₃); IR (CHCl₃) v: 669.1, 928.7, 946.8, 1046.6, 1107.3, 1215.8,1345.5, 1394.2, 1468.5, 1716.8, 1770.6, 2928.6, 3019.9, 3393.1 cm⁻¹; ¹HNMR (CDCl₃, 200 MHz): δ 3.15-3.33 (m, 2H), 3.48 (br s, 1H), 4.07 (t,J=4.9 Hz, 1H), 4.44 (br s, 1H), 4.82 (d, J=15.0 Hz, 1H), 4.89 (d, J=15.0Hz, 1H), 5.09(s, 2H), 5.52 (d, J=8.1 Hz, 1H), 6.02 (d, J=8.0 Hz, 1H),6.94 (d, J=8.1 Hz, 1H), 7.20 (d, J=1.3 Hz, 1H), 7.33 (d, J=1.3 Hz, 1H),7.36-7.49 (m, 5H), 7.66-7.75 (m, 2H), 7.79-7.88 (m, 2H), 9.15 (br s,1H); ¹³C NMR (CDCl₃, 50 MHz): δ 40.87 (t), 61.74 (t), 70.22 (t), 76.64(s), 84.72 (d), 87.01 (d), 93.61 (s), 102.96 (d), 120.74 (d), 123.51(3C, d), 128.40 (d), 128.67 (2C, d), 129.38 (2C, d), 131.33 (d), 131.89(s), 134.18 (3C, d), 137.51 (s), 138.70 (s), 139.35 (s), 139.95 (s),143.07 (s), 150.85 (s), 163.00 (s), 167.96 (2C, s); ESI-MS (m/z): 590.41(100%, [M+Na]⁺); Anal. Calcd for C₃₁H₂₅N₃O₈: C, 65.60; H, 4.44; N,7.40%; Found: C, 65.51; H, 4.31; N, 7.31%

Example 12

1-[3-C,3-O-{o-(2-phenyl-4-(3-aminophenyl))phenylenemethylene}-β-D-ribofuranosyl]uracil(59): By following procedure C, cycloaddition of the diyne 36 (20 mg,0.052 mmol) with 3-amino phenyl acetylene (3.77 mmL, 0.052 mmol) gave 59(22.2 mg, 85% yield) as a Yellowish liquid, [α]_(D) ²⁵+15.8 (c 0.5,CHCl₃); IR (CHCl₃) v: 669.2, 928.9, 1018.4, 1215.7, 1385.1, 1523.9,1694.6, 2924.8, 3020.1, 3437.0 cm⁻¹; ¹H NMR (CDCl₃+CD₃OD, 400 MHz): δ3.07 (dd, J=7.3, 11.9 Hz, 1H), 3.14 (dd, 4.2, 11.9 Hz 1H), 4.04 (dd,J=4.2, 7.3 Hz, 1H), 4.28 (d, J=8.2 Hz, 1H), 5.04 (d, J=13.0 Hz, 1H),5.08 (d, J=13.0 Hz, 1H), 5.09 (s, 2H), 5.40 (d, J=8.1 Hz, 1H), 5.90 (d,J=8.2 Hz, 1H), 6.58 (dd, J=1.8, 8.2 Hz, 1H), 6.60 (d, J=1.3, 8.1 Hz,1H), 6.80 (s, 1H), 6.84 (d, J=7.8 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 7.16(s, 1H), 7.30 (s, 6H); ¹³C NMR (CDCl₃+CD₃OD, 100 MHz): δ 61.73 (t),70.21 (t), 76.15 (d), 85.45 (d), 86.33 (d), 92.68 (s), 102.37 (d),113.86 (d), 114.86 (d), 117.49 (d), 118.50 (d), 127.69 (d), 127.98 (2C,d), 129.33 (2C, d), 129.40 (d), 129.64 (d), 130.66 (s), 138.13 (s),139.68 (d), 139.72 (s), 140.45 (s), 141.87 (s), 142.55 (s), 146.29 (s),150.88 (s), 163.83 (s); ESI-MS (m/z): 622.44 (100%, [M+Na]⁺); Anal.Calcd for: C₂₈H₂₅N₃O₆: C, 67.33; H, 5.04; N, 8.41%; Found: C, 67.31; H,4.97; N, 8.53%

Example 13

1-[3-C,3-O-{o-(2-^(n)hexyl-4-phenyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(60): Procedure C was followed. Diyne 37 (50 mg, 0.128 mmol) and phenylacetylene (13.07 mmL, 0.128 mmol) were used to afford 60 (49.2 mg, 78%yield) as a white solid, mp: 143-145° C.; [α]_(D) ²⁵+20.9 (c 0.5,CHCl₃); IR (CHCl₃) v: 669.3, 929.0, 1045.5, 1384.9, 1466.2, 1685.8,2852.7, 2923.9 cm⁻¹; ¹H NMR (CDCl₃, 200 MHz): δ 0.88 (t, J=6.5 Hz, 3H),1.26-1.47 (m, 6H), 1.56-1.76 (m, 2H), 2.65-2.89 (m, 2H), 3.51 (dd, J=3.9Hz, 2H), 3.81 (dd, J=7.5, 12.1 Hz, 1H), 4.38 (dd, J=3.9, 7.2 Hz, 1H),4.62 (d, J=8.1 Hz, 1H), 5.14 (d, J=12.7 Hz, 1H), 5.22 (d, J=12.7 Hz,1H), 5.80 (dd, J=1.5, 8.1 Hz, 1H), 5.91 (d, J=8.0 Hz, 1H), 7.37-7.57 (m,7H), 9.33 (br s, 1H) ppm; ¹³C NMR (CDCl₃, 50 MHz): δ 14.06 (q), 22.62(t), 29.73 (t), 31.68 (t), 31.94 (t), 33.52 (t), 61.70 (t), 71.97 (t),76.38 (d), 86.52 (d), 89.16 (d), 92.26 (s), 103.20 (d), 117.50 (d),127.15 (2C, d), 127.71 (d), 128.57 (d), 128.84 (2C, d), 132.26 (s),138.02 (s), 140.28 (s), 140.38 (d), 141.59 (s), 142.56 (s), 150.76 (s),163.00 (s); ESI-MS (m/z): 515.65 (100%, [M+Na]⁺); Anal. Calcd forC₂₈H₃₂N₂O₆: C, 68.28; H, 6.55; N, 5.69%; Found: C, 68.17; H, 6.47, N,5.73%

Example 14

1-[3-C,3-O-{o-(2-^(n)hexyl-4-^(n)hexyl)phenylenemethylene}-β-D-ribofuranosyl]uracil(61): General procedure C was followed. Diyne 37 (20 mg, 0.051 mmol) and1-octyne (7.55 mmL, 0.051 mmol) were used to afford a 61 (19.2 mg, 75%yield) as a Colorless liquid, [α]_(D) ²⁵+4.4 (c 0.5, CHCl₃); IR (CHCl₃)v: 669.1, 928.9, 1045.1, 1215.6, 1385.0, 1461.8, 1521.2, 1697.5, 2858.4,2929.9, 3020.1 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 0.87 (t, J=6.4 Hz, 3H),0.88 (t, J=6.4 Hz, 3H), 1.26-1.38 (m, 12H), 1.53-1.71 (m, 4H), 2.47 (dd,J=7.7, 8.1 Hz, 2H), 2.60-2.66 (m, 1H), 2.72-2.74 (m, 1H), 3.43 (dd,J=3.8, 12.0 Hz, 1H), 3.75 (dd, J=7.6, 12.0 Hz, 1H), 4.32 (dd, J=3.8, 7.6Hz, 1H), 4.56 (t, J=7.8 Hz, 1H), 5.05 (d, J=12.4 Hz, 1H), 5.12 (d,J=12.4 Hz, 1H), 5.76 (d, J=8.0 Hz, 1H), 5.87 (d, J=8.0 Hz, 1H), 6.85 (s,1H), 6.95 (s, 1H), 7.45 (d, 8.0 Hz, 1H), 9.25 (br s, 1H); ¹³C NMR(CDCl₃, 100 MHz): δ 14.05 (q), 14.15 (q), 22.55 (t), 22.62 (t), 28.97(t), 29.69 (t), 31.35 (t), 31.64 (t), 31.68 (t), 31.89 (t), 33.40 (t),35.61 (t), 61.76 (t), 71.95 (t), 76.28 (d), 86.53 (d), 89.13 (d), 92.09(s), 103.15 (d), 118.70 (d), 129.66 (d), 130.42 (s), 137.24 (s), 140.33(d), 140.84 (s), 144.39 (s), 150.69 (s), 162.92 (s) ESI-MS (m/z): 523.27(100%, [M+Na]⁺); Anal. Calcd for: C₂₈H₄₀N₂O₆: C, 67.18; H, 8.05; N,5.60%; Found: C, 67.06; H, 7.97; N, 5.71%;

Example 15

1-[3-C,3-O-{o-(2-^(n)Hexyl-4-^(n)henicosyl)-phenylenemethylene}-β-D-ribo-furanosyl]uracil(62): General procedure C was followed. Diyne 37 (50 mg, 0.138 mmol) and1-tricosyne (42.3 mg, 0.138 mmol) were used to afford compound 62 (66.5mg, 73% yield) as a colorless liquid. [α]_(D) ²⁵+1.9 (c 0.2, CHCl₃); IR(CHCl₃) v: 3020, 2930, 2858, 1698, 1521, 1462, 1385, 1216, 1045, 929,669 cm⁻¹; ^(1H) NMR (CDCl₃, 200 MHz): δ 0.86 (t, J=6.5 Hz, 3H), 0.88 (t,J=6.5 Hz, 3H), 1.24 (s, 36H), 1.30-1.36 (m, 8H), 2.57 (t, J=7.7 Hz, 2H),2.60-2.66 (m, 1H), 2.70-2.79 (m, 1H), 3.33 (br s, 1H), 3.44 (dd, J=4.0,12.1 Hz, 1H), 3.75 (dd, J=7.7, 12.1 Hz, 1H), 4.32 (dd, J=4.0, 7.1 Hz,1H), 4.59 (t, J=7.8 Hz, 1H), 5.07 (d, J=12.1 Hz, 1H), 5.13 (d, J=12.1Hz, 1H), 5.29 (s, 1H), 5.78 (d, J=8.1 Hz, 1H), 5.85 (d, J=8.1 Hz, 1H),6.86 (s, 1H), 6.96 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 8.94 (br s, 1H); ¹³CNMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.1 (q), 22.6 (t), 22.7 (t), 29.3 (t),29.5 (t), 29.6 (t), 29.7 (13C, t), 31.4 (t), 31.7 (t), 31.9 (t), 31.9(t), 33.4 (t), 35.6 (t), 53.4 (t), 61.8 (t), 72.0 (t), 76.2 (d), 86.4(d), 89.3 (d), 92.1 (s), 103.2 (d), 118.7 (d), 129.7 (d), 130.3 (s),137.3 (s), 140.4 (d), 140.8 (s), 144.5 (s), 150.6 (s), 162.7 (s) ppm;ESI-MS (m/z): 733.51 (10%, [M+Na]⁺); Anal. Calcd for C₄₃H₇₀N₂O₆: C,72.64; H, 9.92; N, 3.94; Found: C, 72.51; H, 9.97; N, 4.01%.

Example 16

1-[3-C,3-O-{o-(2-phenyl-4-^(n)hexyl)phenylenemethylene}-β-D-ribopyranosyl]uracil(65): General procedure C was followed. Cycloaddition of the diyne 38(25 mg, 0.065 mmol) with 1-octyne (7.2 mmL, 0.065 mmol) gave compound 65(24.8 mg, 77% yield) as a white solid. mp: 124-126° C.; [α]_(D) ²⁵+85.4(c 1.1, CHCl₃); IR (CHCl₃) v: 2924, 2853, 1686, 1466, 1385, 1046, 929,669 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 0.87 (t, J=6.6 Hz, 3H), 1.27-1.40(m, 6H), 1.60 (quint, J=7.8, 2H), 2.60 (t, J=7.8 Hz, 2H), 3.48 (br s,1H), 3.58 (br s, 1H), 3.65 (t, J=10.5 Hz, 1H), 3.71 (dd, J=5.6, 10.5 Hz,1H), 5.23 (d, J=12.3 Hz, 1H), 5.45 (d, J=12.3 Hz, 1H), 5.61 (d, J=8.2Hz, 1H), 5.74 (d, J=9.3 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.94 (s, 1H),7.03 (s, 1H), 7.32-7.43 (m, 5H), 9.58 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz):δ 14.1 (q), 22.5 (t), 22.7 (t), 31.3 (t), 31.6 (t), 35.6 (t), 67.0 (t),69.4 (d), 73.0 (d), 74.3 (t), 81.8 (d), 93.3 (s), 103.2 (d), 119.9 (d),128.0 (3C, d), 129.2 (2C, d), 130.1 (d), 130.1 (s), 137.5 (s), 139.0(d), 139.3 (s), 141.3 (s), 143.7 (s), 151.1 (s), 163.0 (s); ESI-MS(m/z): 515.08 (75%, [M+Na]⁺), 531.02 (100%, [M+K]⁺); Anal. Calcd forC₂₈H₃₂N₂O₆: C, 68.28; H, 6.55; N, 5.69; Found: C, 68.31; H, 6.60; N,5.76.

Example 17

1-[3-C,3-O-{o-(2-phenyl-4-chloropropyl)phenylenemethylene}-β-D-ribopyranosyl]uracil(67): General procedure C was followed. Diyne 38 (20 mg, 0.052 mmol) and1-chloro-4-pentyne (5.51 mmL, 0.052 mmol) were used to afford compound67 (20 mg, 79% yield) as a white solid. mp: 176-178° C.; [α]_(D)²⁵+114.2 (c 0.5, CHCl₃); IR (CHCl₃) v: 3020, 2925, 1694, 1462, 1385,1215, 1046, 929, 669 cm⁻¹; ¹H NMR (CDCl₃CD₃OD, 500 MHz): δ 1.98 (quint,J=7.5 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 3.24 (d, J=9.5 Hz, 1H), 3.45 (t,J=6.4 Hz, 2H), 3.51 (t, J=8.3 Hz, 1H), 3.61 (d, J=12.1 Hz, 1H), 3.65 (d,J=12.1 Hz, 1H), 5.14 (s, 2H), 6.55 (d, J=8.2 Hz, 1H), 5.60 (d, J=9.5 Hz,1H), 6.67 (d, J=8.2 Hz, 1H), 6.85 (s, 1H), 6.98 (s, 1H), 7.24-7.33 (m,5H); ¹³C NMR (CDCl₃+CD₃OD, 125 MHz): δ 32.2 (t), 33.7 (t), 44.0 (t),66.9 (t), 69.4 (d), 71.4 (d), 73.8 (t), 81.6 (d), 92.8 (s), 102.7 (d),119.9 (d), 127.7 (2C, d), 127.8 (d), 128.8 (2C, d), 129.7 (d), 131.3(d), 137.4 (s), 139.1 (s), 139.3 (s), 141.0 (s), 141.9 (s), 151.1 (s),163.7 (s); ESI-MS (m/z): 506.98 (60%, [M+Na]⁺), 522.94 (100%, [M+K]⁺);Anal. Calcd for C₂₅H₂₅ClN₂O₆: C, 61.92; H, 5.20; Cl, 7.31; N, 5.78%Found: C, 61.88; H, 5.09; Cl, 7.47; N, 5.81%.

ADVANTAGES OF PRESENT INVENTION

A strategy that integrates the conceptual advantages of DOS and themanipulation of chemical functionality at an advanced stage in a targetoriented synthesis could be a valuable tool in new drug discoveryprograms. This needs the identification of a structurally simplifyingtransform(s) at the beginning of the retrosynthetic scheme. Thistransform(s) should comprise multiple bond disconnections resulting in acouple of retrons, amongst which at least one should he easy to accessand manipulate. This provision of manipulation/substrate flexibility atthe final/penultimate steps in the forward synthesis should address thechemical functionality modulation. We exemplify the potential of such anapproach by selecting C(3)-spironucleosides as the targets, wherein thecritical spiroannulation has been executed as the final step andemploying commercial or easily available reagents as the substrates.

What is claimed is:
 1. A process for the preparation of Spiro annulatednucleoside of general Formula I;

where, R (in the base) is selected from H, C₁-C₄ alkyl, halogen, OR, NHR(R═H, COCH₃, COO^(t)Bu); Q=H with the proviso that C—N double bond isabsent, C—Z double bond is present and Z is O; Z is NH₂ with the provisothat C—Z double bond is absent, Q≠H; Z is O with the proviso that C—Ndouble bond is absent; A and A′ are selected from H, lower alkyl —OH,—OAc CH₂OH, —CH₂OAc, —CH₂OPiv, —CH₂OTBS; m and n are integers 0,1 A″ andA′″ are selected from 1,3-dihydroisobenzofuran (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), where R,R′, R″ are selected from H, —OH, halo group, —CH₂OH, —CH₂OAc, —COOH,—COOMe, C1-C30 straight or branched alkyl group, optionally substitutedwith halogen or —OH or —NH2 or —NPhth; phenyl group optionallysubstituted with halogen, amino, nitro, C1-C6 alkyl; with the provisothat when n=1[i.e(CH₂)n=1] and where m=0[i.e(CH₂)m=0], A′″ is absent andA″ is 1,3-dihydro isobenzofuran (1a) or isochroman[3,4-dihydro-1H-benzo[c]pyran] represented by the formula (1b), directlyannulated at C-3, A and A′ are selected from H, lower alkyl, OH, —OAc,—CH₂OH—CH2OAc, —CH₂OPiv, —CH₂OTBS,; and R, R′ and R″ in 1,3-dihydroisobenzofuran (1a) or isochroman [3,4-dihydro-1H-benzo[c]pyran]represented by the formula (1b) are selected from H, —OH, halo group,—CH2OH, —CH2OAc, —COOH, —COOMe, C1-C30 straight or branched alkyl group,optionally substituted with halogen or —OH or —NH2 or —NPhth; phenylgroup optionally substituted with halogen, amino, nitro, C1-C6 alkyl; R(in the base) is selected from H, C1-C4 alkyl, halogen; Q=H with theproviso that C—N double bond ( . . . . ) is absent, C—Z double bond ( .. . . ) is present and Z is O; Z is NH2 with the proviso that C—Z doublebond is absent, Q≠H; Z is O with the proviso that C—N double bond ( . .. . ) is absent; the proviso that when both n=1 and m=1, A″ is absentand A″′ is selected from 1,3-dihydroisobenzofuran of formula (1a)) orisochroman [3,4-dihydro-1H-benzo[c]pyran] represented by the formula(1b), A and A′ are selected from H, lower alkyl, —OH, —OAc, —CH₂OH,—CH₂OAc; R, R′ and R″ in 1,3-dihydroisobenzofuran of formula (1a) orisochroman [3,4-dihydro-1H-benzo[c]pyran] represented by the formula(1b) are selected from H, —OH, —OAc, halo group, —CH2OH, —CH2OAc, —COOH,—COOMe, C1-C30 straight or branched alkyl group, optionally substitutedwith halogen or —OH or —NH2 or —NPhth; phenyl group optionallysubstituted with halogen, amino, nitro, C1-C6 alkyl; R (in the base) isselected from H, C1-C4 alkyl, halogen; Q=H with the proviso that C—Ndouble bond ( . . . . ) is absent, C—Z double bond ( . . . . ) ispresent and Z is O; Z is NH2 with with the proviso that C—Z double bondis absent, Q≠H; Z is O with the proviso that C—N double bond ( . . . . )is absent; with the proviso that both A and A″ can form together1,3-dihydroisobenzofuran (1a) where R, R′ and R″, are selected from H,—OH, halo group, —CH₂OH, —CH₂OAc, —COOH, —COOMe, C1-C30 straight orbranched alkyl group, optionally substituted with halogen or —OH or —NH₂or —NPhth; phenyl group optionally substituted with halogen, amino,nitro, C1-C6 alkyl when m=0[i.e(CH2)m=0], A″′ is absent and A′ isselected from H, lower alkyl, —OH, —OAc, —CH2OH, —CH2OAC, —CH2OMe,—CH2OEt, phenyl optionally substituted with halogen, amino, nitro, C1-C6alkyl, wherein the said process comprising the steps of; a) Preparingsolution of diyne and alkyne in mole ratio ranging between 1:1 to 1:3 ina solvent followed by degassing of solution with dry argon; b) adding acatalyst in mole ratio ranging between 0.02 to 0.05 into the degassedsolution as obtained in step (a) followed by heating at temperature inthe range of 70° C.-90° C. for a period in the range of 6 h-12 h; c)cooling the solution as obtained in step (b) to room temperature rangingbetween 25° C.-30° C. followed by solvent evaporation and purificationto obtain spiroannulated nucleoside.
 2. A process for the preparation ofSpiro annulated nucleoside of general Formula I as claimed in claim 1,wherein the said process comprising the steps of; a) charging of diyenein a solvent in a sealed tube followed by degassing with alkyne; b)adding a catalyst into the solution as obtained in step (a); c) coolingthe reaction mixture as obtained in step (b) at temperature rangingbetween −80° C.-−70° C. followed by bubbling of alkyne for a periodranging between 25 min. to 60 min and sealing of tube; d) transferringthe sealed tube as obtained in step (c) in a steal bomb and heating attemperature ranging between 70° C.-90° C. for a period ranging between 6h-12 h allowed by cooling to room temperature ranging between 25° C.-30°C.; e) evaporating the solvent from reaction mixture as obtained in step(d) and purification to obtain spiroannulated nucleoside.
 3. The processas claimed in claim 1, wherein penultimate nucleoside diynes used instep (a) is selected from the group consisting of furanoside nucleoside,pyranoside nucleoside(1-[3-C-phenylethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil),(1-[3-C-(1-octynyl)-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil), (1[3-C-phenylethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil),1-[3-C-Propynyl/Phenylpropynyl/^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]5-flurouracil),(1[3-C-Propynyl/Phenylpropynyl/^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]5-flurouracil).4. The process as claimed in claim 1, wherein the symmetrical andunsymmetrical alkynes used in step (a) and also in step (c) of claim 2is selected from the group consisting of acetylene (CH≡CH), terminalalkyne of the formula R—C≡CH where R is selected from C1-C30 straight orbranched alkyl groups optionally substituted with halo, —OH, —OAc,—CH2OH; a phenyl group further optionally substituted with lower alkyl,halo, —OH, —OAc; diacetate of 2-butyne-1,4-diol, an alkyne of theformula R″—C≡C—R″′ where R″ and R″′ are selected from either straight orbranched chain alkyl group, —H2OH, —CH2OAc, —COOH, —COOAc, TMS,N-propynepthalimide.
 5. The process as claimed in claim 1, wherein1,3-dihydroisobenzofuran is appended on the sugar moiety of thenucleoside via [2+2+2] cyclotrimerization reaction.
 6. The process asclaimed in claim 1, wherein isochroman [3,4-dihydro-1H-benzo[c]pyran] isappended on the sugar moiety of the nucleoside via [2+2+2]cyclotrimerization reaction.
 7. The process as claimed in claim 1,wherein the spiroannulation of the nucleoside diyne with the symmetricaland unsymmetrical alkyne takes place at C-3 of the furanoside ring. 8.The process as claimed in claim 1, wherein the spiroannulation of thenucleoside diyne with the symmetrical and unsymmetrical alkyne takesplace at C-3 of the pyranoside ring.
 9. The process as claimed in claim1-, wherein catalyst used in step (b) is selected from Wilkinson'scatalyst [RhCl(PPh3)3, Cp*RuCl(cod) and [Rh(cod)2]BF4/(R)-BINAP.
 10. Theprocess as claimed in claim 1, wherein solvent used in step (a) isselected from the group consisting of toluene, xylene, methanol,ethanol, propanols and mixture thereof.
 11. The process as claimed inclaim 1, wherein yield of spiroannulated nucleoside is in the range of71-87%.
 12. The process as claimed in claim 2, wherein penultimatenucleoside diynes used in step (a) is selected from the group consistingof furanoside nucleoside, pyranoside nucleoside(1-[3-C-phenylethynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil),(1-[3-C-(1-octynyl)-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]uracil), (1[3-C-phenylethynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]uracil),1-[3-C-Propynyl/Phenylpropynyl/^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribo-pentofuranosyl]5-flurouracil),(1[3-C-Propynyl/Phenylpropynyl/^(n)Hexylpropynyl-3-O-(2-propynyl)-β-D-ribopyranosyl]5-flurouracil).13. The process as claimed in claim 2, wherein the symmetrical andunsymmetrical alkynes used in step (a) and also in step (c) of claim 2is selected from the group consisting of acetylene (CH≡CH), terminalalkyne of the formula R—C≡CH where R is selected from C1-C30 straight orbranched alkyl groups optionally substituted with halo, —OH, —OAc,—CH20H; a phenyl group further optionally substituted with lower alkyl,halo, —OH, —OAc; diacetate of 2-butyne-1,4-diol, an alkyne of theformula R″—C≡C—R″′ where R″ and R′″ are selected from either straight orbranched chain alkyl group, —H2OH, —CH2OAc, —COOH, —COOAc, TMS,N-propynepthalimide.